NCCN Guideline Update Recommends Adjuvant Ribociclib Plus AI in HR+/HER2– Early Breast Cancer

Shreeram Aradhye, MD

The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines in Oncology for breast cancer to recommend ribociclib (Kisqali) in combination with an aromatase inhibitor (AI) as a Category 1 preferred CDK4/6 inhibitor–based regimen for the adjuvant treatment of patients with hormone receptor–positive/HER2-negative early breast cancer.¹

Version 5.2024 of the Clinical Practice Guidelines in Oncology for breast cancer, released on October 15, 2024, made ribociclib the only CDK4/6 inhibitor recommended by the NCCN for all patients with node-positive disease and for patients with no nodal involvement with high-risk characteristics, including a tumor size larger than 5 cm or tumors sized 2 cm to 5 cm that are either grade 2 with genomic risk/a Ki-67 index of at least 20% or grade 3. A Category 1 recommendation indicates that there are high levels of clinical evidence and uniform consensus among the NCCN about ribociclib as a treatment for these patients.^1,2

“These evidence-based guidelines are helpful to clinicians when determining optimal treatment options for patients,” Shreeram Aradhye, MD, president of development and chief medical officer of Novartis, stated in a news release.¹ “Importantly, the NCCN guideline recommendation of ribociclib in this broad population reaffirms the importance of offering eligible patients with early breast cancer, including those with limited nodal involvement and high-risk N0 disease, a CDK4/6 inhibitor treatment like ribociclib in addition to endocrine therapy to reduce their risk of recurrence.”

In September 2024, the FDA approved adjuvant ribociclib in combination with an AI for the treatment of patients with hormone receptor–positive, HER2-negative stage II and III early breast cancer at high risk of recurrence, including those with node-negative disease. In October 2024, The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion advocating for the approval of the combination in the same patient population.^3,4

The NCCN guideline update followed the presentation of updated findings from the phase 3 NATALEE trial (NCT03701334) during the 2024 ESMO Congress. Data from NATALEE supported the FDA approval and positive opinion from the CHMP recommending the approval of adjuvant ribociclib plus an AI in hormone receptor–positive, HER2-negative early breast cancer at a high risk of recurrence. The study randomly assigned adult patients 1:1 to receive ribociclib plus the nonsteroidal AIs letrozole (Femara) or anastrozole (Arimidex). The primary end point was invasive disease–free survival (iDFS) via STEEP criteria; secondary end points included recurrence-free survival (RFS), distant disease-free survival (DDFS), overall survival (OS), and safety and tolerability.^3-5

Data from the 4-year landmark analysis of NATALEE demonstrated that, at a median follow-up for iDFS of 44.2 months, patients in the combination arm (n = 2549) achieved a significant iDFS benefit compared with those who received AI monotherapy (n = 2552; HR, 0.715; 95% CI, 0.609-0.840; 1-sided P < .0001). The 36-month iDFS rates were 90.8% vs 88.1%, in these respective arms, and the 48-month rates were 88.5% vs 83.6%, respectively.⁵

Findings from subgroup analyses revealed that patients with stage II (HR, 0.644; 95% CI, 0.468-0.887) and stage III (HR, 0.737; 95% CI, 0.611-0.888) disease experienced an iDFS benefit with the addition of ribociclib to an AI. An iDFS benefit was also observed with the addition of ribociclib in patients with N0 (HR, 0.666; 95% CI, 0.397-1.118) and N1 to N3 (HR, 0.731; 95% CI, 0.617-0.866) nodal status.

At a median follow-up for DDFS of 44.2 months, patients in the combination arm experienced a significant DDFS benefit compared with those in the control arm (HR, 0.715; 95% CI, 0.604-0.847; nominal P < .0001). Similarly, at a median follow-up for OS of 44.3 months, the addition of ribociclib to an AI led to a reduction in the risk of death vs AI therapy alone (HR, 0.827; 95% CI, 0.636-1.074; nominal P = .0766).

In terms of safety, any-grade adverse effects (AEs) of special interest occurring in the combination and control arms included neutropenia (62.8% vs 4.5%), liver-related AEs (26.7% vs 11.4%), and interstitial lung disease/pneumonitis (1.6% vs 0.9%). Other clinically relevant any-grade AEs included arthralgia (38.8% vs 44.4%), nausea (23.5% vs 7.9%), headache (22.9% vs 17.2%), and fatigue (22.8% vs 13.5%).

The NCCN guideline update was consistent with the FDA indication for ribociclib plus an AI that was based on findings from the NATALEE trial. The NCCN guidelines also continue to recommend the combination as the only Category 1 preferred CDK4/6 inhibitor–based regimen in frontline hormone receptor–positive/HER2-negative metastatic breast cancer. Ribociclib in combination with fulvestrant (Faslodex) is also a Category 1 preferred regimen for the first- and subsequent-line treatment of patients with hormone receptor–positive/HER2-negative metastatic breast cancer.¹

References

1. Novartis ribociclib (Kisqali) recognized as Category 1 preferred breast cancer adjuvant treatment by NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). News release. Novartis. October 24, 2024. Accessed October 28, 2024. https://www.novartis.com/news/media-releases/novartis-ribociclib-kisqali-recognized-category-1-preferred-breast-cancer-adjuvant-treatment-nccn-clinical-practice-guidelines-oncology-nccn-guidelines
2. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 5.2024. Accessed October 28, 2024. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
3. FDA approves Novartis Kisqali to reduce risk of recurrence in people with HR+/HER2- early breast cancer. News release. Novartis. September 17, 2024. Accessed October 28, 2024. https://www.novartis.com/news/media-releases/fda-approves-novartis-kisqali-reduce-risk-recurrence-people-hrher2-early-breast-cancer
4. Novartis receives positive CHMP opinion for Kisqali to help reduce risk of recurrence in people with HR+/HER2- early breast cancer. News release. Novartis. October 18, 2024. Accessed October 28, 2024. https://www.novartis.com/news/media-releases/novartis-receives-positive-chmp-opinion-kisqali-help-reduce-risk-recurrence-people-hrher2-early-breast-cancer
5. Fasching PA, Stroyakovskiy D, Yardley D, et al. Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (Pts) with HR+/HER2− early breast cancer (EBC): 4-year outcomes from the NATALEE trial. Ann Oncol. 2024;35(suppl_2):S1207. doi:10.1016/j.annonc.2024.08.2251